Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.

中文翻译：

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HLA-DQ 等位基因之间的定性而非定量差异影响器官移植中的 HLA-DQ 免疫原性

延长移植器官的寿命对于解决这种救生资源的短缺至关重要。慢性排斥反应以及同种异体移植物不可逆的死亡通常是由供体特异性 HLA 抗体的产生引起的。目前，人们提倡对受者和供者之间的分子（氨基酸）不匹配进行计数，以识别出现 HLA 抗体风险较高的患者，用于器官分配和免疫抑制最小化策略。我们建议不要将此类方法纳入临床使用，并假设并非所有分子错配都同样有助于产生供体特异性免疫反应。在此，我们记录了先前研究设计中的统计缺陷：例如，使用缺乏产生供者特异性抗体（HLA 相同）能力的个体作为阴性队列的一部分。我们使用 CRISPR-Cas9 编辑的细胞提供实验证据，反驳 HLAMatchmaker eplets 代表“功能表位”的说法。我们进一步使用了独特的患者亚组，即接受具有两个 HLA-DQ 错配的同种异体移植物但仅针对一个错配 (2MM1DSA) 产生抗体的患者，以询问差异免疫原性。我们的结果表明，DQα05-异二聚体的错配表现出最高的免疫原性。此外，我们证明 DQα 链对 DQ 分子的整体质量至关重要。最后，我们的数据表明，开发供体特异性 HLA-DQ 抗体的风险增加取决于受体和供体之间的定性（进化和功能）差异，而不仅仅是分子不匹配的数量。总体而言，我们提出了一种免疫学机制原理来解释 HLA-DQ 免疫原性的差异，以及对自身免疫和感染等其他病理过程的潜在影响。